Direct production of enaminones from terminal alkynes via rhodium-catalyzed reaction of formamides with N-sulfonyl-1,2,3-triazoles

Article abstract of DOI:10.1021/ol5010774

A rhodium-catalyzed reaction of formamides with N-sulfonyl-1,2,3-triazoles is developed to formulate a new one-pot procedure for the direct synthesis of α-amino enaminones from terminal alkynes.

Full text of DOI:10.1021/ol5010774

Letter
pubs.acs.org/OrgLett
Direct Production of Enaminones from Terminal Alkynes via
Rhodium-Catalyzed Reaction of Formamides with N‑Sulfonyl-1,2,3-
triazoles
Tomoya Miura,* Yuuta Funakoshi,† Takamasa Tanaka,† and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed reaction of formamides with N-
sulfonyl-1,2,3-triazoles is developed to formulate a new one-pot
procedure for the direct synthesis of α-amino enaminones from
terminal alkynes.
naminones serve as versatile intermediates for the
Esynthesis of a wide variety of heterocycles contained in
biologically active compounds,1 and their synthesis from readily
available starting materials has been an area of active
research.2−4 Now, we report a simple method for the synthesis
of enaminones from terminal alkynes, N-sulfonyl azides, and
formamides. Of note is that three different bonds, i.e., a C−N
single bond, a CO double bond, and a CC double bond
the expected 2-amino-4-oxazoline but α-amino-substituted
are installed regioselectively across the CC triple bond in one
enaminone 5aa was formed exclusively and isolated in 95%
yield after chromatographic purification.12 The reaction
pot (Figure 1).
proceeded even at room temperature. The formal metathesis
of a CC triple bond and a CO double bond occurs with
the simultaneous incorporation of an amino substituent.
We propose the following mechanism for the unexpected
formation of the enaminone 5aa from triazole 1a and DMF
(4a) (Scheme 1). Initially, reversible ring−chain tautomeriza-
Figure 1. Construction of enaminones from terminal alkynes by
introducing three different bonds.
tion of the triazole 1a generates α-diazo imine 1a′, which reacts
with rhodium(II) to afford α-imino rhodium carbene complex
Scheme 1. Proposed Mechanism for the Formation of
Enaminones 5aa
N-Sulfonyl-1,2,3-triazoles react with transition metal com-
plexes to generate α-imino metal carbene complexes,5 which
react with various compounds of nucleophilic character.6 Even
formyl groups are nucleophilic enough to add to the carbenoid
carbon. For example, a reaction with simple aldehydes produces
4-oxazolines.7 On the other hand, α,β-unsaturated aldehydes
give rise to 2,3-dihydropyrroles.8 Fokin et al. recently reported
that ketones were formed with the use of relatively stereo-
demanding secondary amides.9 These studies led us to examine
the use of tertiary formamides as the nucleophilic partner10
with the expectation of the production of the corresponding 2-
amino-4-oxazolines. Thus, 1-mesyl-4-phenyl-1,2,3-triazole (1a)
was prepared from phenylethyne (2a) and mesyl azide (3a)
according to the authentic procedure using copper(I)
thiophene-2-carboxylate (CuTC).11 Then, the triazole 1a
(0.20 mmol) was mixed with N,N-dimethylformamide (DMF;
4a, 1.1 equiv), a rhodium pivalate dimer (1.0 mol %), and 4 Å
molecular sieves (MS) in chloroform (2 mL), and the mixture
was heated at 60 °C for 1 h (eq 1). Much to our surprise, not
Received: April 14, 2014
Published: April 28, 2014
© 2014 American Chemical Society
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Letter
A with extrusion of molecular nitrogen. Nucleophilic addition
of the formyl group of 4a to the electrophilic carbene center
gives zwitterionic intermediate B. The anionic rhodium releases
an electron pair, which induces the imino nitrogen to attack the
carbon of the iminium ion, producing 4-oxazoline intermediate
C.7 The C−O bond of the N,O-hemiaminal moiety is cleaved,
and the resulting zwitterionic species D recyclizes to aziridine
intermediate E. Finally, the aziridine ring is opened to rearrange
into the enaminone 5aa.13
With respect to the substituent on the sulfonyl group, p-tolyl,
benzyl, and 2-(1,3-dioxan-2-yl)ethyl14 groups are all suitable
(eq 2). The product 5ba was a crystalline compound, and its
structure was confirmed by a single-crystal X-ray analysis.
(entries 1−5). Of note was that even alkyl-substituted triazoles
1j−l gave the products 5ja−la in high yields, despite the
possibility of a 1,2-hydride shift occurring with the rhodium
carbene complex (entries 6−8).15
Whereas it has been reported that 1-cyclohexenyl-substituted
triazole 1n16 undergoes an intramolecular cyclization to give
2,3-fused pyrrole in the absence of DMF,17 it underwent the
intermolecular reaction with DMF selectively to give divinyl
ketone 5na, which is suggestive of the relatively strong
nucleophilicity of DMF.18 Interestingly, a prolonged reaction
time caused the ensuing Nazarov cyclization to afford 2-
cyclopentenone 7.
When the reaction of 1b was carried out at 120 °C under
microwave irradiation, 2-amino-oxazole 6 was isolated in 9%
yield in addition to the enaminone 5ba (eq 3). The formation
of 6 is consistent with elimination of p-toluenesulfinic acid from
the 4-oxazoline intermediate corresponding to C, which
supports the mechanism shown in Scheme 1.
The synthetic applicability of the present reaction was
demonstrated by the reaction using the substrate 1o derived
from 5α-cholestan-3-one (eq 5).
Various triazoles 1 were subjected to the reaction with DMF
at 60 °C (Table 1). Triazoles 1e−i possessing an aryl group at
the 4-position all reacted well to afford the corresponding
products 5ea−ia in high yields ranging from 92% to 97%
Table 1. Rh(II)-Catalyzed Reaction of Various Triazoles 1e−
a
m with DMF (4a)
Various tertiary formamides prepared from acyclic and cyclic
secondary amines successfully participated in the reaction with
the 1-mesyltriazole 1a, and the corresponding products were
obtained in good to high yields (Scheme 2). However,
secondary formamides derived from primary amines such as
N-methylformamide failed to participate in the reaction. This is
probably because the −NH group either directly adds to the
rhodium carbene complex A or provides the imino nitrogen of
intermediate B with a proton.9
With the reaction of formamides with triazoles in hand, we
next developed an all-in-one-pot synthesis of enaminones
starting from terminal alkynes (Table 2). Substrates 2a, 3a, and
4a, copper(I) and rhodium(II) catalysts, and chloroform were
put in a reaction vessel, and the mixture was stirred at room
temperature. After 6 h, 2a and 3a were both consumed to
generate triazole 1a. Then, the reaction mixture was stirred at
60 °C for 1 h, and the following chromatographic purification
afforded the enaminone 5aa in 83% isolated yield based on the
triazole 1
R1
entry
product 5
yield (%)
1
2
3
4
5
6
7
8
9
4-Me-C6H4
4-MeO-C6H4
4-MeO2C-C6H4
4-CF3-C6H4
3-thienyl
1e
1f
5ea
5fa
97
93
b
1g
1h
1i
5ga
5ha
5ia
94
92
93
c
nHex
1j
5ja
91
c
BzO(CH2)4
(phth)N(CH2)4
EtO
1k
1l
5ka
5la
91
c
92
c
1m
5ma
56
a
1 (0.20 mmol), 4a (0.22 mmol), Rh2(OCOtBu)4 (2.0 μmol), and MS
b
c
(40 mg) in CHCl3 (2 mL). 3 h. 4a (1.0 mmol) in CHCl3 (0.5 mL).
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isolated in moderate to good yields through a single workup/
purification procedure (entries 2−9).
Synthetic utilities unique to the enaminone 5aa were
exemplified by further derivatizations shown in Scheme 3. A
Scheme 2. Rh(II)-Catalyzed Reaction of Triazoles 1a with
Various Formamides 4b−j
a
Scheme 3. Synthetic Derivatizations of Enaminone 5aa
a
reaction with butylamine caused replacement of the dimethy-
lamino group at the β-position to furnish secondary amine 8,
which was difficult to prepare by using N-butylformamide in
the present reaction. Various heterocycles such as pyrimidine 9,
pyrazole 10, and isoxazole 11 were readily synthesized by
treatment with guanidine, phenylhydrazine, and hydroxylamine,
respectively.
b
The same reaction conditions with those in Table 1. Toluene (2
mL) at 100 °C.
Table 2. All-in-One-Pot Synthesis of 5 Starting from
Terminal Alkynes 2
a
In summary, we have developed a new method for the
synthesis of α-amino enaminones, which serve as useful
building blocks for the construction of various nitrogen-
containing frameworks. Terminal alkynes can be used as
starting materials, and multiple functionalities are regioselec-
tively installed across the CC triple bonds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral data for the new compounds,
details of the X-ray analysis, and CIF file. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tmiura@sbchem.kyoto-u.ac.jp.
*E-mail: murakami@sbchem.kyoto-u.ac.jp.
Author Contributions
†These authors contributed equally.
Notes
a
b
c
On a 0.20 mmol scale. CH2ClCH2Cl (2 mL). 4a (0.60 mmol) in
The authors declare no competing financial interest.
CHCl3 (1 mL).
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Biing-Jiun Uang (National
Tsing Hua University) in celebration of his 60th birthday. We
thank Dr. Y. Nagata (Kyoto University) for his kind help in the
X-ray analysis. This work was supported by MEXT (Grant-in-
Aid for Scientific Research on Innovative Areas Nos. 22105005
and 24106718, Young Scientists (A) No. 23685019, Scientific
Research (B) No. 23350041) and JST (ACT-C).
alkyne 2a (entry 1). Similar results were obtained when the
reaction of 2a was carried out on a 10 mmol scale or even at
room temperature.19 This one-pot procedure minimizes
generation of waste solvents.
Various enaminones 5 were synthesized from other
combinations of terminal alkynes 2 and formamides 4 and
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(9) Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.; Fokin, V.
V. J. Am. Chem. Soc. 2014, 136, 195.
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